PhD defence T. (Tingting) Chen

The secret life of mitochondria: intercellular transfers in neuroprotection, biomarker discovery, and oncogenesis

Mitochondria are essential organelles for maintaining cellular health, with recent studies revealing their ability to transfer between cells. Only a limited number of articles showing the biological function of extracellular mitochondria. This thesis explores the physiological role of mitochondria transfer through three distinct pathways: free mitochondria, extracellular vesicles (EVs), and tubular structures. We demonstrate that transferring freshly isolated free mitochondria rescues neuronal cells from ferroptosis by reducing oxidative stress, preventing cell death, and restoring neuronal networks. Using microfluidic devices, we revealed that mitochondria can travel from axonal networks to cell bodies, suggesting potential therapeutic applications for administering mitochondria peripherally. On the other hand, we preformed proteomic analysis to analyze proteins in EVs derived from neural progenitor cells (NPCs) prepared from an Alzheimer’s disease (AD) patients. Our results revealed several potential proteins involved in AD pathology, including pregnancy zone protein (PZP), alkaline phosphatase (ALPL), periostin (POSTN), apolipoprotein C-III (APOC3), and transferrin (TF). Moreover, we identified several mitochondrial matrix proteins upregulated in AD EVs, reflecting impaired mitochondrial function and the propagation of stress signals. Lastly, we showed that neuronal mitochondria transfer to glioblastoma (GBM) cells via tubular structures, enhancing cancer cell survival and proliferation, a strategy how tumors can exploit in the brain. In summary, we demonstrate the biomedical function of extracellular mitochondria attributes to their sources: healthy mitochondria promote repair and survival, while stressed cells dispose damaged components, potentially spreading pathological signals. These findings provide new insights into mitochondrial biology and the therapeutic potential of extracellular mitochondria.